Phosphoric acid dichlorides of compounds having a bactericidal action and process for the manufacture of same



Fatented June 23, 1942 OFFICE Kurt Warnat, Basel, Switzerland, assignor to Hofimann-La Roche Inc., Nutley, N. J., a corporation of New Jersey No Drawing. Application July 24, 1939, Serial No. 286,298. In Germany July 30, 1938 9 Claims. (Cl. 260-3973) Phosphoric acid dichlorides of the general formula ChPONROS OzNRB.

in which R represents alkyl or hydrogen, R. alkyl, aryl or hydrogen, and R" alkyl or hydrogen, are obtained by heating amino benzene sulphonamides with phosphorus oxychloride. By reaction with alkalis, ammonia or amines, the phosphoric acid dichlorides thus obtained can be transformed into phosphoric acids or phosphamic acids of -amino benzene sulphonamides having a strong bactericidal action which do not cause any irritation. These acids form easily soluble neutral salts which may be used for injection purposes.

It has now been found that also with other bactericidal compounds containing sulphur and possessing one or several amino groups phosphoric acid dichlorides can be obtained on heating with phosphorus oxychloride. If several amino groups are present, each of them is substituted by a phosphoric acid dichloride radical. The sulphurous amino compounds having a bactericidal action can be heated with phosphorus oxychloride themselves or in the form of their salts. The mono or polyphosphoric acid dichlorides obtained represent important intermediate products in the manufacture of easily soluble non-irritating medicinal preparations. They are obtained by treatment of mono or polyphosphoric acid dlchlorides with alkalis, ammonia or amines. v

The following compounds, for instance, may be used for carrying out the process: Derivatives of sulphanilic acid amide, such as 4-amino benzene sulphonyl sulphanilamide amide) and 4-amino benzene sulphonyl sulphanilic acid dimethyl amide; bactericidal deriva- (disulphaniltives of arylalkyl sulphides, sulphoxide and sulphones, such as 4-amino thiophenol propyl ether.

Example 1 20 parts by weight of 4-amino benzene sulphonyl sulphanilic acid dimethyl amide are boiled for some time with 50 parts by weight of phosphorus oxychloride. When still warm, the clear solution is stirred into a mixture of 100 parts by weight of benzene and 100 parts by weight of petroleum ether. The resulting phosphoric acid dichloride of the formula of phosphorus oxychloride until a solution is ob-' tained. The liquid is then poured into a mixture of 400 parts by weight of benzene petroleum ether whereupon the reaction product solidifies. It is triturated with petroleum ether, sucked oil and dried invacuo. The resulting product is of the formula C12PONHC6H4SOZNHC6H4NHPOC12 and, with alkalis, ammonia or amine, splits of! 4 molecules of hydrochloric acid on conversion. into the corresponding phosphoric acid derivatives. It is also decomposed by moist air and water.

Example 3 i 20 parts by weight of sulphanilic acid-4-nitroanilide are boiled with parts by weight of lo tives of sulphanilic acid anilides, such as sulphaghosphomg P f E S e fii g g 2L 2 nilic acid- 4 -nitroanilide, sulphanilic acid -4 m a pa Y we g 0 e aminoanilide and sulphanilic acid-3-aminopetmlewm 1 The reaction anmde sulphurous compounds having a not is sucked oil and dr1ed 1n vacuo- It hasthe tericidalac ion without sulphonamide groups. formula CIZPONHCGI-RSOZNHCSHNOL on desuch as derivatives of diaryl sulphides, diaryl disulphides and the corresponding sulphoxides and sulphones, for instance 4,4-diamino diphenyl sulphide, 4,4'-diamino diphenyl sulphoxide, 4,4- diamino diphenyl sulphone, 4-amino-4'-nitrodiphenyl sulphone; also bactericidal derivatives of diarylsulphide (sulphoxide, sulphone) sulphonamides, such as, for instance, 4-amino diphenyl sulphide 4-sulphonamide, 4 amino diphenyl sulphone-4-su1phonarnide; bactericidal derivacomposition it splitsoff 2 molecules'of hydrochloric acid. 7 v r Example 4 20 parts by weight of 4,4'-diamlno diphenyl sulphide are boiled for some time with parts by weight of phosphorusoxychloride and the clear solution stirred into a mixture of 300 parts by weight of benzene petroleum ether. The reaction product solidifies and, after decanting the liquid, triturated with parts by weight of petroleum ether. It is sucked off, washed with petroleum ether and dried in. vacuo. The resulting compound has the formula By reaction with alkalis, ammonia or amines, 4 molecules of hydrochloric acid are split off on conversion into the corresponding phosphoric acid derivatives.

Example 5 parts by weight of 4,4'-diamino diphenyl sulphoxide are boiled with 30 parts by weight of phosphorus oxychloride until solution sets in. The liquid is poured into a mixture of benzene petroleum ether and the solidified reaction product triturated with petroleum ether. It is then sucked off and dried in vacuo. It has the formula C12PONHC6H4SOC6H4NHPOC12. On decomposition 4 parts by weight of hydrochloric acid are split off.

Example 6 10 parts by weight of ii-amino benzene sulphonyl sulphanilic acid amide are boiled with parts by weight of phosphorus oxychloride. The hot solution is poured into a mixture of 100 parts by-weight of benzene and 100 parts by weight of petroleum ether whereby the resulting dichloride of the formula solidifies. It is triturated with petroleum ether, sucked off and dried in vacuo. It decomposes in moist atmosphere and, with alkalis, ammonia or amines. splits off 2 molecules of hydrochloric acid.

Example 7 10 parts by weight of 4,4'-diamino diphenyl sulphone are boiled with parts by weight of phosphorus oxychloride until a solution is obtained. The liquid is poured into a mixture of benzene petroleum ether. 'The solidified reaction product is triturated with petroleum ether. It is sucked off and dried in vacuo. It has the formula ClzPONHCsH4SO2CsH4NI-IPOC12. On decomposition with alkalis or ammonia 4 molecules of hydrochloric acid are split off.

I claim:

1. Compounds of the formula 4. The 4,4'-di-(dichlorophosphamyl)-diphenyl sulphone.

5. Process for the manufacture of compounds of the formula wherein R represents a radical selected from the group consisting of hydrogen, alkyl and aralkyl radicals, R represents a sulphurous radical selected from the group consisting of --SO-, SOe-, and -SO2NH radicals, and R" represents a radical selected from the group consisting of sulphon amido, sulphon alkyl amido, sulphon dialkyl amido, dialkyl amino, acyl amino, and phosphoric acid dichloride amino radicals, said radical R" being in a position selected from the group consisting of 'para and meta positions, comprising heating compounds of the formula with phosphorus oxychloride.

6. Process for the manufacture of compounds of the formula wherein R represents a radical selected from the group consisting of hydrogen, alkyl and aralkyl radicals, R represents a sulphurous radical selected from the group consisting of -SO, -SO2- and SO2NH-- radicals, and'R. represents a radical selected from the group consisting of sulphon amido, sulphon alkyl amido, sulphon dialkyl amido, dialkyl amino, acyl amino and phosphoric acid dichloride amino radicals,

said radical R" being in a position selected from the group consisting of para and meta positions, comprising heating compounds of the formula O cg,

with phosphorus oxychloride, and pouring the reaction mixture into a solvent in which the condensation product is insoluble to isolate the condensation product formed.

7. Process for the manufacture of the phosphoric acid dichloride of -amino benzene sulphonyl sulphanilic acid amide. comprising heating 4-amino benzene sulphonyl sulphanilic acid amide with phosphorus oxychloride.

8. Process for the manufacture of the phosphoric acid dichloride of 4-amino benzene sulphonyl sulphanilic acid dimethylamide, comprising heating i-amino benzene sulphonyl sulphanilic acid dimethylamide with phosphorus oxychloride.

9. Process for the manufacture of the phosphoric acid dichloride of 4,4'-diamino diphenyl sulphone, comprising heating 4.4'-diamino diphenyl sulphone with phosphorus oxychloride.

KURT WARNA'I. 

